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Memorial Sloan Kettering Nears Approval for Liquid Biopsy Test; Describes Validation at AACR

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NEW YORK (GenomeWeb) – Although researchers at Memorial Sloan Kettering Cancer Center have been early adopters of several commercial liquid biopsy assays in the last few years, the institute is now close to launching its own assay, reflecting a strategy it first pursued in tissue genomics with the MSK-IMPACT test.

MSK investigators described their validation efforts for the new test, called MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), at the annual meeting of the American Association for Cancer Research this week. A separate poster also described some early data from use of the assay in a research setting to track minimal residual disease in post-operative colorectal cancer patients.

MSK molecular geneticist Dana Tsui said at AACR that the center made its first submission for NY State Department of Health approval of the tests last November, received its review back from the department on Feb. 25, and has until later this month (60 days from the review return) to re-submit.

As described by Tsui and her coauthors, MSK-ACCESS covers selected exons from 129 cancer-related genes winnowed from the MSK-IMPACT panel.

"Because of our experience [with tissue sequencing] we have extensive infrastructure already established, from consent to processing samples, to bioinformatics, to transferring data into our server and integrating into clinical reports,'" Tsui said during an AACR presentation.

In designing the test, "We wanted to serve the needs of multiple services," she added. "We didn't want to have one test for each cancer type because we would have to validate each test one by one so for us the most efficient [plan was for a] pan-cancer assay."

To choose the genes to include, investigators focused on regions associated with available and investigational drugs, known hotspot sites, regions with high mutation rates, protein kinase domains, and tumor suppressor genes.

SNPs are included to measure zygosity and copy number in 13 genes, as are common SNPs that define genome-wide copy number and aid in quality control. Targets also cover introns for detection of structural variants in 10 genes like NTRK and FGFR, which have emerged as "very important drug targets." The panel also includes microsatellite instability regions so the test can give an MSI-high or -low readout to guide immunotherapy prescription.

According to Tsui, even though MSK-ACCESS is less than a quarter of the size of the IMPACT test, it still covers most variants that are being routinely reported as part of MSK's tumor tissue testing.

As liquid biopsy has advanced, increasing attention (including previous studies by MSK researchers) is being paid to the phenomenon of clonal hematopoiesis of indeterminate potential (CHIP), whereby mutations accumulate in cancer-associated genes in small clonal populations of white blood cells

While some other marketed tests, like Guardant360, rely only on sequence data and associated bioinformatics to help identify and eliminate CHIP, Tsui said that MSK-ACCESS adds a second layer of definition — sequencing white blood cells both to correct for CHIP and to help distinguish somatic from germline mutations.

During her presentation at AACR, Tsui described the methods that the group employed to improve sensitivity and reduce errors for the MSK-ACCESS panel, including what the team describes as duplex unique molecular indexing (UMI) or barcoding and background error suppression.

In the team's method, barcodes attach to both strands of a double-stranded molecule, such that if there is a true mutation it will be present on both strands, helping to silo and eliminate amplification and stochastic errors.

Using ultra-high depth (>15,000x) sequencing, investigators were able to show in their validation experiments for NY State approval that MSK-ACCESS can detect low-frequency (0.1 percent) variants with high confidence.

Although the institution is currently working with Illumina HiSeq2500s, Tsui said that she and her colleagues validated the ACCESS assay in parallel on both the 2500 and the NovaSeq 6000 because they expect to make the switch to the latter platform in the near future.

For the current application with the NY State DOH, Tsui said validation focused on 11 genes of primary clinical relevance, with the plan being to continue to validate the rest of the panel once the center can launch it in its CLIA lab for this initial more limited indication.

In addition to reporting on validation of the assay, MSK investigators also shared a brief report at the meeting on one potential clinical application of the test — detecting and monitoring minimal residual disease in patients who have had their tumor surgically removed.

Because of the potential for such monitoring to enable more effective adjuvant therapy trials, this is an area of increasing attention, with at least one company — Natera — having already commercialized a service for which it is now working to gain reimbursement.

'We have initiated clinical trials in multiple tumor types to evaluate the benefit of early therapeutic intervention in patients where MSK-ACCESS can detect circulating tumor DNA following surgery," investigators wrote. As a proof of concept, the group used ACCESS to monitor nine colon adenocarcinoma patients, analyzing blood samples for variants known from these patients' tissue tumor sequencing. 

According to the investigators, circulating tumor DNA was detected in 66 percent (six of nine) pre-surgical samples and it remained present in half of these patients after surgery.